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Objectives: To evaluate the variation of hospital rates of delayed epinephrine administration in pediatric patients with nonshockable in-hospital cardiac arrest, and the association of those rates with event, 24-hour, and overall survival to hospital discharge.

Design: A retrospective evaluation was performed. Delayed epinephrine was defined as greater than 5 minutes between the time the need for chest compressions was identified and epinephrine was administered. The main outcome was the association of hospital rate of delayed epinephrine administration with survival to hospital discharge. Secondary outcomes were event and 24-hour survival. Evaluation used hierarchical logistic regression and included 13 patient/event-level and seven hospital-level factors.

Setting: Hospitals with greater than 6 months data in the American Heart Association’s Get With the Guidelines—Resuscitation registry (2000–2016) and greater than or equal to five total pediatric cardiac arrests with nonshockable rhythm.

Patients: Children less than 18 years old with index nonshockable in-hospital cardiac arrest treated with greater than or equal to one epinephrine dose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal).

Members of the American Heart Association's Get With The Guidelines Resuscitation Investigators can be viewed in the Acknowledgments.

Supported, in part, by the Congenital Heart Surgical Unit at Medical City Children’s Hospital.

Dr. Praestgaard’s institution received funding from Medical City Children’s Hospital. Dr. Parshuram disclosed that he holds shares in a clinical decision support company in part owned by the Hospital for Sick Children, but no money has been paid to him. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Approximately 16,000 children in the United States have a cardiac arrest each year, predominantly in a hospital setting (1, 2). An initial rhythm of pulseless electrical activity or asystole (i.e., nonshockable rhythm) is most common and is associated with significant mortality, with only 25–40% of patients surviving to hospital discharge (1, 3–5). Despite efforts in resuscitation research and improvement in outcomes after in-hospital pediatric resuscitation during the last 30 years (4–6), there are few evidence-based interventions besides supportive care for pediatric cardiac arrest patients with a nonshockable rhythm (6, 7).

The most recent 2015 American Heart Association (AHA) Guidelines Update for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care by the “International Liaison Committee On Resuscitation Pediatric Life Support Task Force” stated that it is reasonable to consider administering a 0.01 mg/kg dose of IV/intraosseous epinephrine every 3–5 minutes during pediatric cardiac arrest (6). A recent report found that delay in epinephrine administration for adult in-hospital, nonshockable cardiac arrest was associated with decreased chance of return of spontaneous circulation (ROSC), survival to discharge, and good neurologic outcome (8). Similarly, a recent multicenter cohort study of pediatricin-hospital cardiac arrest (IHCA) reported that delayed epinephrine administration was associated with a decreased chance of ROSC, 24-hour survival, survival to hospital discharge, and survival to hospital discharge with a favorable neurologic outcome among patients with an initial nonshockable rhythm (9). It is conceivable that hospital efforts aimed at improving timely administration of epinephrine could potentially improve survival in this population where survival rates have been traditionally poor.

Among children with IHCA, the extent of hospital variation in delayed epinephrine administration and its impact on hospital survival rates is largely unknown, a critical step toward sharing best practices so that all centers can improve their care of patients with cardiac arrest. To address this gap in knowledge, we used data from the Get With The Guidelines–Resuscitation (GWTG-R) registry to examine hospital-level variation in rates of delayed epinephrine administration. We then examined the implications of hospital variation by determining the association between a hospital’s rate of delayed epinephrine administration and its rate of overall survival for pediatric patients with nonshockable IHCA. We hypothesized that there will be substantial variation among hospitals in rates of delayed epinephrine administration for pediatric IHCA due to a nonshockable rhythm and that hospitals with higher rates of delayed epinephrine administration will have lower rates of survival. An improved understanding of current hospital performance in epinephrine administration times and factors associated with delayed epinephrine administration is critical for developing effective interventions that could be implemented at hospitals to improve outcomes after pediatric IHCAs.

MATERIALS AND METHODS

Data Source

We used data from the GWTG-R registry, which is an AHA sponsored, prospective, quality improvement registry of IHCA in the United States. The data collection process and reliability have been described in extensive detail previously (10–14). In the registry, cardiac arrest is defined as pulselessness, or a pulse with inadequate perfusion, requiring chest compressions and/or defibrillation, with a hospital-wide or unit-based emergency response by acute care facility personnel. Cases are identified, and data extracted by trained personnel from cardiac arrest flow sheets, hospital paging system logs, routine checks of code carts, pharmacy drug records, and hospital billing charges for resuscitation medication (15). The registry uses Utstein-style templates for cardiac arrest, standardized reporting guidelines used to define patient variables and outcomes, to facilitate uniform reporting across hospitals (16, 17). Hospital-level data were obtained from the American Hospital Association’s Annual Survey from 2013 (18).

Study Population

The cohort included events submitted to the GWTG-R registry between January 2000 and December 2016. We included all patients younger than 18 years old who received chest compressions while pulseless with a documented nonshockable initial rhythm (pulseless electrical activity or asystole) and who received at least one epinephrine bolus during the resuscitation. We included index events only from hospitals with at least 6 months of reporting and at least five pediatric cases with initial nonshockable rhythm reported. We excluded patients with the following: 1) cardiac arrest in the delivery room; 2) an illness category of trauma or hospital visitor; 3) vasopressor (epinephrine, norepinephrine, phenylephrine, and/or dopamine [for dopamine, at least 3 μg/kg/min]) infusion at the time of cardiac arrest; 4) treatment with extracorporeal membrane oxygenation during the event; 5) vasopressin received before epinephrine; 6) epinephrine given before loss of pulse; 7) epinephrine received after ROSC; 8) epinephrine given more than 20 minutes after loss of pulse; 9) missing data on covariates; 10) missing data on time to first epinephrine dose; and 11) missing data on in-hospital survival. Exclusion criteria were chosen based on prior work by Andersen et al (9). Our final cohort comprised 1,462 patients at 69 hospitals (Fig. 1).

Study Variables and Outcomes

The primary outcome measure was the relationship between the hospital rate of delayed epinephrine administration and survival to hospital discharge. Based on current guideline recommendations for administration of epinephrine (6) and prior work (9), delayed epinephrine administration was defined as more than 5 minutes between the time at which the need for compressions was identified and the administration of epinephrine. Secondary outcomes were the relationship between delayed epinephrine administration and ROSC (defined as at least 20 min with a palpable pulse), 24-hour survival, and survival with favorable neurologic outcome. Neurologic outcome was assessed in survivors with the use of the Pediatric Cerebral Performance Category (PCPC) score (19), where a PCPC score of 1 indicates no neurologic deficit, 2 mild cerebral disability, 3 moderate cerebral disability, 4 severe cerebral disability, and 5 coma or vegetative state. A PCPC score of 1–2 was considered a favorable neurologic outcome, and a PCPC score of 3–5 or death was considered a poor neurologic outcome. However, there is currently no universal definition of a favorable neurologic outcome in pediatric cardiac arrest patients using the PCPC score, and multiple definitions have been used previously (4, 11, 14).

Patient-level information included age, gender, and illness category. Cardiac arrest event characteristics included initial rhythm of asystole or pulseless electrical activity (PEA), location (ICU, telemetry, nonmonitored ward), time of day (daytime vs after hours), day of the week (weekday vs weekend), calendar year of admission, time to initiation of chest compressions, time to epinephrine administration, whether the event was witnessed or monitored, interventions in place at the time of cardiac arrest (e.g., mechanical ventilation), and whether an endotracheal tube was inserted during the event. Hospital-level characteristics included total number of hospital beds, proportion of ICU beds, geographic region, teaching status, type of hospital (primarily children or primarily adult), eligible arrests per 1,000 pediatric admissions, and number of years of GWTG-R participation. These 13 patient/event-level characteristics and the seven hospital-level characteristics are summarized in eTable 1 (Supplemental Digital Content 1, http://links.lww.com/PCC/A859).

Statistical Analyses

For each event, we calculated the time interval to epinephrine administration to be the difference between the time of first epinephrine administration and the time of cardiac arrest in minutes. We then calculated the hospital rates of delayed administration to be the number of hospital events with time to epinephrine administration greater than 5 minutes divided by the number of IHCA events reported by that hospital. We conducted univariate analyses of the associations between patient/event- and hospital-level characteristics and quartiles of hospital rates of delayed epinephrine administration using Pearson chi-square tests of significance for categorical variables and Kruskal-Wallis tests for continuous ones. We then constructed a multivariable hierarchical regression model adjusting for significant univariate associations (p < 0.05) of patient/event- and hospital-level characteristics with hospital rates of delayed epinephrine administration. In this multilevel model, we included hospital site as a random effect and adjusted for five patient/event-level and two hospital-level characteristics as fixed effects. We used the median odds ratio (OR) to quantify the extent to which hospital variation in rates of delayed administration of epinephrine can be explained by differences in hospital characteristics. In general, the median OR is obtained from a multivariable model that incorporates only patient/event-level variables, is always at least one, does not have a CI, and permits meaningful comparisons between aggregate hospital-level characteristics and patient/event-level variables. For example, a median OR of 1.5 suggests that the odds of delay in epinephrine administration for a patient are 50% higher at one randomly selected hospital than at another randomly selected hospital for a similar patient. After quantifying the extent to which differences across hospitals explain the variation in rates of delayed epinephrine administration, we added hospital characteristics to the previously selected patient/event-level variables to build our final multivariable regression model.

Last, we examined the extent to which variation in rates of delayed epinephrine administration across hospitals was associated with both patient/event-level survival and hospital-level survival. In the event-level models, we considered event-level ROSC, 24-hour survival, survival to discharge, and survival to discharge with favorable neurologic outcome to be dependent variables and included hospital rates of delayed epinephrine as an additional covariate in the previously described two-level hierarchical regression models. For the hospital-level analyses, we fit multivariable regression models in which we considered hospital rates of ROSC, 24-hour survival, survival to discharge, and survival to discharge with favorable neurologic outcome to be dependent variables and hospital bed size and hospital rates of delayed epinephrine to be independent variables (20–23).

For all analyses, the null hypothesis was evaluated at a two-sided significance level of .05 with 95% CIs. All analyses were conducted with SAS statistical software (Version 9.4; SAS Institute Inc, Cary, NC). The study was reviewed by the Medical City Dallas Institutional Review Board, which waived the requirement for informed consent.

Sensitivity Analysis

We conducted four sensitivity analyses to determine the robustness of our findings. First, to determine whether our findings were influenced by our definition of delayed epinephrine administration, we repeated the analysis of our primary outcome using a threshold of 3 minutes instead of 5 minutes to define delayed epinephrine administration. Second, given that delays in epinephrine administration and other aspects of resuscitation response may differ in patients who arrest in an ICU in comparison with patients who arrest outside an ICU, we repeated our primary analysis of hospital variation in epinephrine administration and its association with survival after restricting our cohort only to patients with the IHCA event in an ICU. Our third sensitivity analysis limited our cohort to patients with an IHCA event outside the ICU, and last, we repeated the primary analysis after restricting our cohort to include hospitals with greater than or equal to 10 eligible events instead of greater than or equal to five eligible events.

RESULTS

We identified 1,462 pediatric patients (> 18 yr) at 69 hospitals with an IHCA due to a nonshockable rhythm who were not receiving vasopressors at the time of the arrest and who received at least one dose of epinephrine between 2000 and 2016 in an eligible hospital (Fig. 1). Overall, 218 of 1,462 patients (14.9%) had a time to epinephrine administration of more than 5 minutes. The proportion of events with delayed epinephrine administration varied widely across hospitals and ranged from 0% to 80% (median, 15.6%; interquartile range, 7.1–25%) (Fig. 2). Tables 1 and 2 summarize patient and hospital characteristics across hospital quartiles of delayed epinephrine administration. Hospitals were categorized into quartiles based on the proportion of events with delayed epinephrine administration as follows: Q1, 0% to < 7.1%; Q2, 7.1% to < 15.6%; Q3, 15.6% to < 25%; and Q4, 25–80%.

The results of our sensitivity analyses closely aligned with those of our primary analysis. We redefined delayed epinephrine administration using a cutoff of greater than 3 minutes rather than greater than 5 minutes after onset of cardiac arrest. In these analyses, delayed epinephrine administration remained inversely correlated with ROSC (ρ = −0.52, p < 0.001) and 24-hour survival (ρ = −0.51; p < 0.001) but was also inversely correlated with survival to discharge (ρ = −0.43; p < 0.001). After restricting the CPA events to an ICU location only, the number of events was reduced from 1,462 to 917 and the number of hospitals reduced to 48. In this subcohort, the proportion of events with delayed epinephrine administration ranged from 0% to 40%, suggesting less variability than in the main study sample. Hierarchical regression analyses for this subcohort found no association with delayed epinephrine administration and outcomes, noting that patient-level survival outcomes do not vary as much when the analysis is restricted to the ICU. Restricting CPA events to those occurring outside the ICU yielded a subcohort of 395 events and 31 hospitals. After hierarchical regression model adjustment for patient- and hospital-level characteristics, higher hospital epinephrine delay rates were significantly associated with worse patient-level survival at 24 hours (p = 0.0028) and survival to discharge (p = 0.035), but not with ROSC (p = 0.20). We were not able to fit a hierarchical regression model for the survival to discharge with favorable neurologic outcome because of the limited sample size. Finally, the cohort was limited to hospitals with greater than or equal to 10 cases rather than greater than or equal to 5 cases of nonshockable IHCA, which reduced the number of events from 1,462 to 1,278 and the number of hospitals from 69 to 40. These analyses noted that at the hospital level delayed epinephrine administration was associated with worse 24-hour survival and survival to hospital discharge. Throughout all analyses, hospitals in the “worst” quartile with respect to delayed administration of epinephrine were associated with much lower survival rates, both at the patient and hospital levels, than other hospitals.

DISCUSSION

In a large, multicenter registry of pediatric IHCAs, we found large variation in the timely administration of epinephrine for patients with an initial nonshockable rhythm of pulseless electric activity or asystole, with overall hospital rates of delayed epinephrine ranging from 0% to 80%. The observed hospital-level differences in delayed epinephrine administration can only partly be explained by certain patient and cardiac arrest event characteristics. Importantly, hospital-level differences explain a certain amount of this variation; however, many of the individual hospital characteristics that we explored—such as cardiac arrest volume, academic status, and type of hospital—were unrelated to hospital performance in delayed epinephrine administration. In multivariable analyses, there were two patient/event-level predictors of delayed epinephrine administration, asystole, and insertion of an endotracheal tube. Among traditional hospital factors evaluated, only bed size less than 200 beds compared to greater than or equal to 500 beds and ICU location were associated with differences in rates of delayed epinephrine administration. We also found that hospital rates of ROSC, 24-hour survival, and survival to discharge were lower at hospitals with more frequent delays in epinephrine administration than in hospitals where such delays were less common. Throughout all analyses, hospitals in the “worst” quartile with respect to delayed administration of epinephrine were associated with much lower survival rates, both at the patient and hospital-level, than other hospitals.

In recent adult (8) and pediatric (9) patient-level analysis, delay in administration of epinephrine for IHCA with an initial nonshockable rhythm was associated with worse outcomes. Patients with a nonshockable initial rhythm and prompt administration of epinephrine had improved ROSC, short-term survival, survival to hospital discharge, and survival to hospital discharge with a promising neurologic outcome as compared to patients who had a delay in initial epinephrine dose. These associations remained when accounting for multiple predetermined potentially confounding patient, event, and hospital characteristics and in multiple different sensitivity analyses in both studies (8, 9). Our study adds to this growing literature for pediatric IHCA by showing marked hospital-level variation in delays to epinephrine administration for nonshockable pediatric IHCA. Hospitals with lower rates of delay to epinephrine administration had higher rates of ROSC, 24-hour survival, and survival to hospital discharge than those hospitals with higher rates of delayed epinephrine administration.

The physiologic rationale for early administration of epinephrine in patients with cardiac arrest is strong, particularly in those with rhythms not amenable to defibrillation. Epinephrine is a potent peripheral vasoconstrictor as well as a coronary artery vasodilator. This combination of physiologic effects results in an increase in coronary perfusion pressure, which has been shown to be strongly associated with ROSC in both animals and humans (24, 25). Epinephrine is currently recommended in pediatric cardiac arrests as the first-line pharmacologic intervention despite no randomized placebo-controlled trials in this patient population (26, 27). One randomized placebo-controlled study in the adult out-of-hospital cardiac arrest population found improved ROSC and short-term survival with administration of epinephrine (28). However, the study was underpowered to detect any difference in long-term outcome because of unanticipated lack of enrollment (29).

Unlike adults, pediatric CPA is more likely to be secondary to respiratory failure and shock, rather than a primary cardiac etiology, with the most common presenting rhythm being PEA or asystole. Yet, overall survival outcomes in children after IHCA are superior to adults despite fewer shockable rhythms (3). The prospective trial by Tibballs and Kinney (5) demonstrated that 90% of pediatric IHCA had an initial cardiac rhythm of PEA, asystole, or bradycardia. Studies have also demonstrated that use of epinephrine during resuscitation has significant effect on rhythm changes during resuscitation. In patients with PEA as an initial rhythm, epinephrine can improve ROSC but increases the rate of rhythm transitions, including transient ROSC, during resuscitation and may render the patient more unstable overall (30).

Current guidelines recommend administration of epinephrine as soon as vascular or intraosseous access is obtained and subsequently every 3–5 minutes for patients with a nonshockable rhythm (6). Therefore, the variation in rate of delayed epinephrine administration observed in our study was particularly striking, with a median OR of 1.23. Although higher volume is associated with improved outcomes for a number of surgical and medical procedures, we did not find a relationship between IHCA volume and delayed time to epinephrine administration (31–34). Thus, we cannot conclude that a lack of institutional experience at low-volume pediatric resuscitation sites is an important underlying factor. This is in contrast to an adult GWTG-R study evaluating hospital variation in delayed epinephrine administration in adult nonshockable IHCA, which found delays in epinephrine administration were more common at hospitals with low cardiac arrest case volume than in high-volume hospitals (35). Thus, we may not point toward a lack of institutional experience at low-volume pediatric sites with regard to resuscitation care as an important underlying factor. We did not find an association between hospital structural factors such as teaching status or type of hospital (primarily children or primarily adult) with delays in epinephrine administration. This is similar to a previous study showing substantial hospital variation in rates of delayed defibrillation for adult IHCA attributable to shockable rhythm (36). Similar to our study, delays in defibrillation were not associated with hospital structural characteristics, with the exception of bed size and ICU location, as was noted in our study. The paucity of conventional hospital-level characteristics associated with performance of epinephrine administration time may reflect a true opportunity for future improvement because it suggests the importance of process of care measures in achieving best practices. These findings suggest that hospital processes of care may be more important in determining hospital quality. Indeed, many of the characteristics we evaluated are not even readily amenable to modification (e.g., admission volume, academic status, geographic region, and type of hospital). The association between bed volume and epinephrine administration time seen in this study may actually reflect the impact of quality improvement efforts or even active intervention trials to improve resuscitation outcomes at larger hospitals rather than the hospital size itself.

As noted above, when the multivariable model was adjusted for individual hospital-level characteristics, an ICU arrest location was associated with lower rates of delayed epinephrine administration. Additionally, on sensitivity analysis after restricting the CPA events to an ICU location only, there was less variability in epinephrine delay rates than in the main study sample, and hierarchical regression analyses found no association with delayed epinephrine administration and outcomes in this cohort. However, when we looked at events occurring outside the ICU, the hierarchical regression model noted that higher hospital epinephrine delay rates were significantly associated with worse patient-level survival at 24 hours and survival to discharge. As noted in the outcomes table and the correlations figure, it is the events in the fourth quartile or highest rate of epinephrine delay that are vastly different from the events in the other three quartiles of delay. Looking at differences in characteristics in this fourth quartile, the higher rates of tracheal intubation may relate to lower rates of mechanical ventilation at the time of arrest (i.e., you cannot intubate the de novo arresting child who is already intubated on a mechanical ventilator). Children on mechanical ventilation must also be in the ICU, so not surprisingly the fourth quartile has the least number of children in the ICU at the time of IHCA. Hence, this “worst outcome” quartile consists of a large group of children not in the ICU, and not on mechanical ventilation with the lowest rate of monitoring and witnessed arrest. Thus, is the delay in epinephrine merely a marker for not being in the ICU, not being witnessed/monitored at the time of the IHCA, and as a result having a less prepared/educated/trained staff where epinephrine dosing is forgotten? Another factor to consider is that the majority of these hospitals are primary adult hospitals, and are these children being kept on the floor at these centers who would normally be transferred to an ICU or monitored area in a pediatric focused hospital? This may be easily addressed with the increasing use of electronic medical record-based systems that identify higher acuity and/or deteriorating patients and in some cases automatically activating a rapid response or medical emergency team. The failure to recognize the deteriorating child could be remedied in an automated fashion and could initiate transfer of the child to a dedicated children’s hospital if no suitable PICU/step down bed is available at that hospital.

LIMITATIONS

A number of limitations should be considered when interpreting the current study. First, the data are observational, and the possibility of unmeasured confounding remains. We tried to account for this by multivariable regression modeling, including adjusting for patient, event, and hospital-level characteristics. Second, we excluded a small number of patients based on missing values for covariates, time to epinephrine, or the outcomes, which might decrease the generalizability of our results. Third, GWTG-R is a quality improvement registry, and hospital participation is voluntary. Given the fact that a minority of children’s hospitals in the United States participate in the registry and hospitals in a quality improvement registry are more likely to direct substantial resources to improving CPR outcomes, our findings may not be generalizable to nonregistry hospitals. Fourth, although our model adjusted for several patient, event and hospital characteristics, we did not have information on certain factors. For instance, we did not have information on hospital factors such as staffing ratios, presence of around-the-clock intensivists in critical care units, and use of mock codes and other quality improvement initiatives. It is possible that delays in epinephrine administration are confounded by other components of CPR efforts, including quality of chest compressions, which is difficult to quantify and is not measured in GWTG-R. Fifth, functional status has been inferred from PCPC scores at discharge. Although a favorable PCPC score at discharge is associated with improved long-term survival (19), patient performance on dedicated scales for neurologic assessment were not available, and we were therefore only able to assess functional status. Additionally, a PCPC score was only reported in 60% of survivors. Finally, the cohort was restricted to a specific pediatric patient population which consisted of 1,462 patients among 19,957 pediatric IHCA events (7.3%) and did not include those patients receiving vasopressors at the time of the arrest, thus these results may not be generalizable to different pediatric patient populations who suffer IHCA.

CONCLUSIONS

Although delays in epinephrine administration following pediatric IHCA with an initial nonshockable rhythm of pulseless electric activity or asystole are common, there is substantial hospital variation in rates of delayed epinephrine administration. Differences across hospitals explained a substantial degree of the variation in rates of delayed epinephrine administration, but few facility characteristics were found to explain this variation. Asystole and insertion of an endotracheal tube were the only patient/event-level predictors of delayed epinephrine administration, and bed volume less than 200 beds compared with greater than or equal to 500 beds and ICU location were the only hospital-level characteristics found to be associated with delayed epinephrine administration. Hospital rates of ROSC, 24-hour survival, and survival to discharge are inversely correlated with hospital rates of delayed epinephrine. After adjusting for relevant factors, patient- and hospital-level delayed epinephrine administration was associated with lower event and 24-hour survival across increasing quartiles of epinephrine delay. Given extensive differences in epinephrine administration time across institutions and the recognized impact of delayed epinephrine on survival, new approaches to improve hospital performance in epinephrine administration time could represent a critical area for quality improvement. Further studies are needed to determine if improving hospital performance on time to epinephrine administration, especially at hospitals with poor performance on this metric, will lead to improvement in outcomes.

14. Ortmann L, Prodhan P, Gossett J, et al; American Heart Association’s Get With the Guidelines–Resuscitation Investigators: Outcomes after in-hospital cardiac arrest in children with cardiac disease: A report from Get With the Guidelines–Resuscitation. Circulation 2011; 124:2329–2337